Especially, 2-{2-methyl-4-[({4-metyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-yl}methyl)sulfonyl]phenoxy}acetic acid (hereinafter, called to “GW501516”) among thiazole derivatives of formula (XI) showed an excellent effect to treatment of obesity in animal models (Cell 2003, 113, 159), and proved effectiveness in cardiovascular disease by increasing high density lipoprotein (HDL) and decreasing low density lipoprotein (LDL) effectively in the animal experiment (Proc. Natl. Acad. USA 2001, 98, 5306) and in clinical trial. And the process for preparation of the said substance has been disclosed in PCT publication WO 01/00603A1 and Bioorg. Med Chem. Lett. 2003, 13, 1517, in which GW501516 (13) was prepared, as shown in the following scheme(1). Methyl (4-mercapto-3-methylphenoxy)acetate (7), synthesized from the starting material, 4′-hydroxy-3′-methylacetophenone (1), via 6 steps, was coupled to 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)thiazole (11), which was prepared from 4-(trifluoromethyl)thiobenzamide (8) via 3 steps, in the presence of excessive cesium carbonate to obtain the methyl ester (12) of GW501516, and then treating the ester with 1 N lithium hydroxide to give GW501516.

As an alternative synthesis method of GW501516, it is disclosed as illustrated in the following scheme (2), that the compound (13) of GW501516 can be prepared by introducing ethyl acetate group to o-cresol (14), reacting the resulted coruppund (15) with sulfonyl chloride, reducing the resulted compound (16) with tin (Sn) under acidic condition to form ethyl (4-mercapto-2-methyl phenoxy)acetate (17), reacting it with 5-chloromethyl-4-methyl-2-(4-trifluoromethyl phenyl)thiazole (11) together with an excessive cesium carbonate to obtain the ethyl ester intermediate (18) of GW501516, and deprotecting the ester group of the intermediate compound with 1 N lithium hydroxide.

Although the above compound (13) has known to be an excellent efficacy in the treatment of obesity in animal models and in the treatment of disease states associated with cholesterol metabolism in clinical trials, the manufacturing method thereof was not satisfactory, thereby being not cost-effective. That is to say,                1) The manufacturing method of reaction scheme (1) consists of 12 steps, and the total yield thereof is as low as 2%. So, it is not proper to be applied to the industry, due to its extreme low production yield.        2) The manufacturing process according to the reaction scheme (1) includes three refluxing steps at elevated temperature for 16 hours, which takes long time to obtain the final product.        3) Tin (Sn) powder used in reaction scheme (2) is very unstable to the moisture, and moreover, it is a combustible metal, thereby being very dangerous to adopt it in industrial scale.        4) An excessive tin (Sn) powder used in the reaction scheme (2) may lead to pollution of the environment.        5) A separated another step for reacting compound (11) with compound (7) or compound (17) in the reaction scheme (1) or (2) is required, and also an excess amount of cesium carbonate, which is not common inorganic base, is used, and also the reaction time is comparatively long.        6) The hydrolysis steps of methyl or ethyl ester using 1 N lithium hydroxide in reaction scheme (1) or (2) requires a long reaction time, about 16 hours, of which yield is as low as 60%.        7) Methyl or ethyl (4-mercapto-2-methylphenoxy)acetate (7) or (17) obtained as an intermediate compound in the reaction scheme (1) or (2) is unstable, so the respective compound can be easily changed to disulfides, which results in lowering the total reaction yield.        
Under the circumstance, the novel process for preparing the above compound with easiness and low cost has been demanded in the art.